The goal of this SBIR Phase 2 application is to continue the development and evaluation the intrathoracic pressure regulator (ITPR), intended to increase circulation and blood pressure clinically significant states of hypotension, including cardiac arrest and septic shock. This novel non-invasive device is inserted within a standard respiratory circuit between the patient and a means to ventilate the patient. It functions by decreasing intrathoracic pressure during the expiratory phase to subatmospheric levels after each positive pressure ventilation. The decrease in intrathoracic pressure, typically to -7 to -9 mmHg, creates a vacuum within the thorax relative to the rest of the body thereby a) significantly enhancing blood return to the heart and consequently increasing cardiac output and blood pressure and b) uniquely lowering intracranial pressure thereby increasing cerebral perfusion. Phase 1 pre-clinical studies demonstrated significantly improved survival and neurological outcome without adverse effects when using the ITPR to treat cardiac arrest and hemorrhagic shock. Recent pilot studies in humans with intra-operative hypotension provide support for the potential for this innovative technology to have a significant clinical benefit. Building further upon our recent and significant progress with this device including studies in animal models of cardiac arrest, hemorrhagic shock, and septic shock, the specific aims of this research include: 1) demonstrate proof of clinical concept that application of CPR and an active ITPR device in cardiac arrest patients will augment key physiological parameters including mean femoral systolic and diastolic arterial blood pressure, oxygen saturation, and end tidal carbon dioxide values when compared to patients treated with a sham ITPR device and CPR;2) demonstrate proof of clinical concept that application of an active ITPR in patients undergoing a) general abdominal surgery and b) hepatic resection surgery will augment key hemodynamic parameters including systolic and diastolic arterial blood pressure and mean arterial pressure when compared hemodynamic values when a sham ITPR is used;and 3) refine the device design to address current and future clinical needs by: a) designing and manufacturing a commercial version of the ITPR device that can be easily inserted into an anesthesia circuit or attached to a resuscitator bag and vacuum source that includes a manometer, a means to quickly disengage and reengage the device and includes a gas sampling port;b) designing, manufacturing, and bench testing a prototype of an enhanced version of the ITPR (eITPR) capable of providing 3 phases of therapy: positive pressure breath during the inspiratory phase, negative intrathoracic pressure during the first portion of the expiratory phase and then positive end expiratory pressure (PEEP) during the secondary portion of the expiratory phase;and c) evaluating the long-term effects of the commercial version of the ITPR and the eITPR on lung function in an animal model of lung injury. A positive CPR trial would result in a new tool to help save tens of thousands more lives per year after cardiac arrest in the US alone. Positive intra-operative studies promise to decrease morbidity and mortality for patients inside and outside the hospital with severe hypotension secondary to blood loss and other life-threatening causes. In addition, the proposed product enhancement work proposed in Aim 3b and 3c will provide a means to treat patients with ITPR therapy who have underlying pulmonary disease, thereby significantly expanding the potential clinical value of this novel non-invasive treatment modality for clinically significant and life-threatening hypotension. PUBLIC HEALTH RELEVANCE: Despite advances in the treatment of patients with life-threatening hypotension from traumatic injuries, trauma remains the number one cause of death among Americans between the ages of 1 and 44 and the fourth leading cause of death overall. The economic consequence of these injuries is estimated at 40 billion dollars in direct costs and over 400 billion dollars per year in productive life years. The main objective of this Phase 2 proposal is to provide proof of concept evidence in two carefully designed clinical studies that a novel device, the intrathoracic pressure regulator (ITPR), can rapidly counteract the effects of severe hypotension. As such, this new device has the potential to be an important new advance in treating life-threatening hypotension and thereby reduce civilian and military mortality rates.